When a drug quietly vanishes, nobody touched itThe Mystery of Why Some Drugs Vanish

A drug molecule can flip into a new crystal form and make the original impossible to reproduce, costing Abbott an estimated $250 million on ritonavir alone.

You follow the recipe to the letter, and the pie comes out of the oven as a cobbler. Drug manufacturing does this for real: during crystallisation the product turns into a different polymorph — same chemical formula, different shape and behaviour.

Nobody touched it and it is still gone

Abbott's ritonavir, approved for HIV/AIDS in 1996, sold Form I in gel capsules. In 1998 Form II took over; it dissolved less readily and was ineffective, so Abbott pulled the drug, reformulated and relaunched it as a caplet in 1999, at a cost of about $250 million.

Stranger still, the new form is not confined to one lab. Anyone trying to make the old one gets the new one instead — and even carrying a sample of the old form into a lab growing the new one is enough to flip it.

When a Canadian drugmaker tried to make Form I of ranitidine (Zantac) after the patent expired, Glaxo sued, arguing any attempt would inevitably leave traces of Form II. Glaxo lost.

One speck of dust can rewrite the recipe

Researchers put it down to thermodynamics: the less stable form grows faster and dominates, until the more stable one appears and seeds everything around it.

The best explanation for the worldwide spread is that tiny seed molecules are floating in the air. Researchers who moved from a Form II lab to a Form I lab were said to carry the curse with them.

In 2024 a team managed to recreate Form I of ritonavir using ball-mill grinding in a protected environment. The drug is not lost for good — but this kind of sorcery is still among chemistry's spookier stories.